High fracture risk after long term oral bisphosphonates and vitamin D

Summary

Introduction: Optimal duration of bisphosphonate (BP) therapy has not been defined. A recent FDA publication suggests periodically re-evaluating patients on BP. Those with low risk may discontinue BP after 3–5 years, those still at high risk may benefit from ongoing BP.

Patients and methods: We compared continued BP therapy plus plain vitamin D to BP plus alfacalcidol in patients still at a significantly increased fracture risk after an average of 4.3 years of BP plus plain vitamin D use over two more years. The study was based on retrospective chart analysis and followed 214 patients (167 female, 47 male). Among these 145 continued alendronate (ALN) and 69 risedronate (RIS). In addition, group A (n = 106) received 800 IU/d plain vitamin D plus 1200 mg/d calcium as before, while patients in group B (n = 108) were switched from plain vitamin D to 1 μg/d alfacalcidol plus 500 mg/d calcium. The respective proportions of males and females and patients with ALN or RIS intake did not differ between group A and B. BMD was measured at 0, 12 and 24 months at lumbar spine (LS) and femoral neck (FN) by DXA. Lateral spine morphometry assessed prevalent and incident vertebral fractures. Recorded were the number of falls and fallers 2 years before and during the trial, back pain (VAS 0–10), adverse events (AE) and prevalent and incident non-vertebral fractures. We also conducted subgroup analyses in four groups – female, male, ALN, RIS on all endpoints.

Results: BMD at LS did not change significantly over two years with +1.1 % in group A, but increased significantly with BP plus alfa-calcidol by + 5.5 % (B vs. A p < 0.01). At the FN site the respective changes were +0.6 % and +3.4 % (p < 0.01). The average number of falls per patient-year was reduced by 12 % in A (ns) and by 44 % in B (p < 0.03). There was a significant decrease in average back pain score with BP plus alfa calcidol vs. BP plus plain vitamin D after two years (p < 0.02). The number of patients with new vertebral fractures did not significantly differ between A and B. There were however significantly less non-vertebral fractures with alfacalcidol (p < 0.05). The above was found significant in all subgroups for nearly all endpoints. The number of adverse events (AE) did not differ between groups. No serious AE were observed.

Discussion: The data show that in male and female osteoporosis patients still at risk after 4.3 years on oral BP a continuation of BP plus alfacalcidol is superior to ongoing therapy with BP plus plain vitamin D.

Zusammenfassung

Einleitung: Die optimale Dauer einer Bisphosphonat (BP)-Therapie ist bislang nicht eindeutig definiert. In einer aktuellen Publikation der amerikanischen FDA wird empfohlen, den Status von BP-Patienten in regelmäßigen Intervallen zu überprüfen und bei niedrigem Frakturrisiko nach drei bis fünf Jahren die BP-Therapie zu unterbrechen, bei hohem Risiko fortzuführen.

Patienten und Methoden: Wir verglichen bei Patienten mit nach 4,3 Jahren BP weiterhin hohem Frakturrisiko die fortgesetzte BP-Anwendung plus natürliches Vitamin D versus Alfacalcidol über zwei weitere Jahre. Die Studie basierte auf retrospektiver Aktenauswertung von 214 Patienten (167 Frauen, 47 Männer). Entsprechend der Vortherapie führten 145 die orale BP-Therapie mit Alendronat (ALN), 69 mit Risedronat (RIS) fort. Zusätzlich erhielt die Gruppe A (n = 106) 800 IE Vitamin D plus 1200 mg Kalzium und Gruppe B (n = 108) 1 μg Alfacalcidol und 500 mg Kalzium pro Tag. Die jeweiligen Anteile an Frauen und Männern und ALN- und RIS-Patienten waren für die beiden Gruppen nicht unterschiedlich. Die Knochendichtewerte (BMD) wurden zu Beginn und nach 12 und 24 Monaten an der Lendenwirbelsäule (LS) und am Oberschenkelhals (FN) mit DXA bestimmt. Mittels lateraler Wirbelsäulen-Morphometrie (DXA) wurden vorbestehende und neu auftretende Wirbelfrakturen erfasst. Weiterhin wurde die Anzahl der Stürze und die Patientenzahl mit Stürzen vor und während der Studie dokumentiert, Rückenschmerz-Score (VAS 0–10), unerwünschte Effekte (AE) sowie die Anzahl nichtvertebraler Frakturen. Zusätzlich wurden bezüglich aller Endpunkte auch Subgruppen-Analysen durchgeführt für Frauen, Männer, ALN und RIS.

Ergebnisse: Die LS-BMD änderte sich über die zwei Jahre mit + 1,1 % nicht signifikant in Gruppe A, jedoch in Gruppe B mit BP plus Alfacalcidol um + 5,5 % (B vs. A p < 0,01). Am FN-Messort betrugen die entsprechenden Änderungen + 0,6 % und + 3,4 % (p < 0,01). Die mittlere Sturzhäufigkeit pro Patientenjahr nahm in Gruppe A um 12 %, in Gruppe B um 44 % ab (p < 0,03). Die mittlere Abnahme des Rückenschmerz-Scores war ausgeprägter für BP plus Alfacalcidol nach zwei Jahren (p < 0,02). Während die Häufigkeit neuer vertebraler Frakturen nicht signifikant zwischen den beiden Therapiegruppen differierte, zeigt die Alfacalcidol-Gruppe signifikant weniger nichtvertebrale Frakturen (p < 0,05). Entsprechende Befunde ergaben sich für nahezu alle Endpunkte auch für die Subgruppen. Die Anzahl und Art der AE war für beide Gruppen nicht unterschiedlich und schwerwiegende AE wurden nicht mitgeteilt.

Diskussion: Die Ergebnisse zeigen, dass bei weiblichen und männlichen Osteoporose-patienten, die nach 4,3 Jahren BP noch ein erhöhtes Risiko haben, eine geänderte Therapiekombination mit Alfacalcidol einer Weiterführung mit natürlichem Vitamin D deutlich überlegen ist.

Keywords

Osteoporosis - long-term bisphosphonate - treatment continuation - vitamin D - alfacalcidol

Schlüsselwörter

Osteoporose - langfristige Bisphosphonat-Therapie - Behandlungsfortsetzung - Vitamin D - Alfacalcidol

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